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(Hypertension. 1995;26:70-77.)
© 1995 American Heart Association, Inc.

Articles

In Vivo Characterization of Muscarinic Receptor Subtypes That Mediate Vasodilatation in Patients With Essential Hypertension

Tobias A. Bruning; Peter C. Chang; Maarten G.C. Hendriks; Pieter Vermeij; Martin Pfaffendorf; Pieter A. van Zwieten

From the Department of Nephrology, University Hospital Leiden (T.A.B., P.C.C.); Department of Pharmacotherapy, Academic Medical Centre, Amsterdam (T.A.B., M.G.C.H., M.P., P.A. van Z.); and Department of Clinical Pharmacy, University Hospital Leiden (P.V.) (the Netherlands).

Correspondence to Tobias A. Bruning, Department of Nephrology, Building 1, C3-P, Room 27, University Hospital Leiden, PO Box 9600, 2300 RC Leiden, Netherlands. E-mail bruning@ RullF2.LeidenUniv.NL.

Abstract Attenuated cholinergic vasodilatation has been suggested as an endothelium-related mechanism involved in essential hypertension. We investigated the role of muscarinic (M) receptor subtypes in the forearm resistance vasculature. In eight white men with essential hypertension and eight matched normotensive control subjects (age of both groups, 47±4 years; mean±SEM), we infused the nonselective agonist methacholine in the presence of saline and the antagonists atropine (nonselective), pirenzepine (M₁-selective), and AF-DX 116 (M₂-selective) into the brachial artery and measured forearm blood flow and forearm vascular resistance using venous occlusion plethysmography. Affinity constants (pK_b values) were determined from calculated plasma concentrations of the infused compounds and EC₅₀ values. Sodium nitroprusside was given as an endothelium-independent control, and minimal forearm vascular resistance after 10 minutes of ischemia was used as a marker of structural vascular changes. Hypertensive patients showed higher minimal forearm vascular resistance, indicating structural vascular changes. However, sodium nitroprusside– and methacholine-induced vasodilatation was similar in both groups, with apparent EC₅₀ values (log moles per liter; mean±SEM) of -7.32±0.13 and -7.51±0.21 in hypertensive patients and -7.37±0.13 and -7.45±0.02 in control subjects, respectively. Atropine, pirenzepine, and AF-DX 116 caused a shift to the right of the concentration-response curve of methacholine, with apparent pK_b values of 8.63±0.08, 6.81±0.13, and 5.51±0.29 in hypertensive individuals and 8.62±0.10, 6.98±0.08, and 5.49±0.09 in control subjects, respectively. Again, there were no statistically significant differences in these pharmacological parameters between hypertensive patients and normotensive subjects. The affinity constants and rank order for potency of the muscarinic antagonists, atropine>pirenzepine>AF-DX 116, indicate that cholinergic vasodilatation in the forearm vascular bed is predominantly mediated by the M₃ receptor subtype. Despite indications for structural vascular changes in hypertensive subjects, the vasodilator responses to both sodium nitroprusside and methacholine were unchanged in these patients. Essential hypertension is not associated with changes in the pharmacological characteristics of muscarinic receptors in forearm resistance vasculature.

Key Words: receptors, muscarinic • hypertension, essential • forearm • plethysmography • endothelium-derived relaxing factor

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